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This phase I/II study evaluated the capacity of tumor microenvironment (TME) gene engineering by intratumoral injection of a viral vector encoding a designed CD40L and 4-1BBL combined with intravenous atezolizumab (anti-PD-L1 antibody) to induce immune activation in 24 patients with stage IV malignant melanoma refractory to PD-1 inhibition. Primary objective was tolerability. Tumor response, pharmacokinetics, and biomarker evaluations were secondary. Treatment was well-tolerated in both dose cohorts (1×10¹¹ and 5×10¹¹ viral particles). Th1 immune biomarkers was increased in the TME (NanoString) as well as in blood (Olink). In long-term survivors, we observed increased markers for T cell fitness and for the immunoproteasome. The overall response rate was 17% accordingly to RECIST 1.1 and disease control was noted in 54%. Forty-six percent of patients were still alive two years post enrollment. The lower dose showed very encouraging results with a median progression-free survival of 9.7 months and median overall survival of 26.3 months (post-hoc analyses). In conclusion, TME gene engineering may have re-sensitized refractory patients to checkpoint treatment or acted alone to control tumor growth. The small sample size and single arm design limits effect interpretation but the data shows promise for continued clinical investigation. Study registration: NCT04123470.